LIF is a new p53 negative regulator.

Abstract

Leukemia inhibitory factor (LIF), a cytokine that belongs to the interleukin-6 family, regulates multiple important biological functions. Recently, we found that LIF is an important negative regulator of p53 in human colorectal cancer cells. LIF negatively regulates p53 protein levels and functions by activation of the Stat3 signaling pathway, which in turn induces the expression of ID1, the helix-loop-helix (HLH) protein inhibitor of differentiation and DNA binding. ID1 increases MDM2 expression at both mRNA and protein levels to accelerate p53 protein degradation. Overexpression of LIF increases chemoresistance of cultured colorectal cancer cells and colorectal xenograft tumors in a largely p53-dependent manner. Furthermore, LIF is overexpressed in a large percentage of human colorectal cancer specimens and LIF overexpression is associated with a poor prognosis in colorectal cancer patients. Our study revealed a new role of LIF in tumorigenesis through regulation of the p53 signaling pathway.